Direct alkenylation of non-aromatic enamides via palladium-catalyzed oxidative coupling: Synthetic developments and applications

Article abstract of DOI:10.1016/j.crci.2013.02.007

Direct C(3) alkenylation of non-aromatic enamides through palladium(II)-catalyzed Fujiwara-Moritani cross-coupling was developed. The reaction scope includes a range of cyclic enamides as well as activated alkenes. The utility of this methodology is illustrated by the synthesis of octa- or tetrahydroquinoline cores obtained from conjugated enamides via Diels-Alder cycloaddition.

Full text of DOI:10.1016/j.crci.2013.02.007

C. R. Chimie 16 (2013) 358–362
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´
Full paper/Memoire
Direct alkenylation of non-aromatic enamides via palladium-catalyzed
oxidative coupling: Synthetic developments and applications
*
Nicolas Gigant, Lae¨titia Chausset-Boissarie, Romain Rey-Rodriguez, Isabelle Gillaizeau
Institut de chimie organique et analytique, Universite´ d’Orle´ans, UMR 7311 CNRS, rue de Chartres, 45067 Orle´ans cedex 2, France
A R T I C L E I N F O
A B S T R A C T
Article history:
Direct C(3) alkenylation of non-aromatic enamides through palladium(II)-catalyzed
Fujiwara–Moritani cross-coupling was developed. The reaction scope includes a range of
cyclic enamides as well as activated alkenes. The utility of this methodology is illustrated
by the synthesis of octa- or tetrahydroquinoline cores obtained from conjugated enamides
via Diels–Alder cycloaddition.
Received 21 December 2012
Accepted after revision 7 February 2013
Available online 15 March 2013
Keywords:
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Alkenylation
Fujiwara–Moritani
Enamides
Oxidative coupling
Diels–Alder
´
´
R E S U M E
Mots cle´s :
´
´
´ ´
´
´
L’alcenylation directe en C(3) d’enamides non aromatiques a ete developpee selon le
couplage croise´ catalyse´ par le palladium(II) de´crit par Fujiwara–Moritani. Le potentiel de
cette re´action s’e´tend sur une large gamme d’e´namides cycliques ainsi que diffe´rents
Alce´nylation
Fujiwara–Moritani
Enamides
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´
´ ˆ
´
´
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alcenes actives. L’interet de cette methodologie est illustree par la synthese de noyaux
Couplage oxydant
Diels–Alder
´
´
´
`
octa- ou tetrahydroquinoleine via une reaction de cycloaddition de Diels–Alder a partir
d’e´namides conjugue´s pre´ce´demment obtenus.
´
´
´
´
ß 2013 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
1. Introduction
process [2]. Although a great number of aromatic
substrates have been employed in the last few years [3],
only a limited substrate scope is reported concerning non-
aromatic substrates with alkenes [4].
Carbon–carbon bond-forming reactions, involving car-
bon–hydrogen activation, are valuable processes and have
become a powerful tool for the formation of more complex
building blocks [1]. Cross dehydrogenative coupling
reaction is a particularly attractive challenge in organic
synthesis as it will not only improve atom economy but
also increase the overall efficiency of multi-step synthetic
sequences. An efficient coupling has been developed by
Fujiwara and Moritani, involving arenes and activated
alkenes through an oxidative palladium(II)-catalyzed
The nitrogen atom is ubiquitous in nature and life
sciences and
p-electron-rich olefins, such as enamides,
are important motifs that have been widely used as
synthons in the synthesis of various compounds [5]. Thus,
the development of convenient as well as step-economi-
cal methodologies for the construction of small but
complex nitrogen-containing molecules, following the
Diversity-Oriented Synthesis (DOS) program [6], is
currently an ongoing project in our laboratory [7]. Indeed,
biological screening requires the upstream rapid synthe-
sis of large numbers of structurally similar compounds.
Within this area, we focused our attention on octa- or
* Corresponding author.
E-mail address: isabelle.gillaizeau@univ-orleans.fr (I. Gillaizeau).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.02.007

N. Gigant et al. / C. R. Chimie 16 (2013) 358–362
359
as an inseparable mixture of regioisomers. The dynamic
hydride elimination derivative was, thus, in fact observed
when the methyl group was present at the -position of
b-
a
the acrylate. The substrate scope was increased by using
various protecting groups on the nitrogen atom and the
nature of the cyclic enamide. Pleasingly, the original
conjugated enamides, 3k–m, were synthesized in good
yields and the protocol was also amenable to endo-
enamides (3n–o). In contrast, the introduction of a C2-
electron-rich phenyl substituent to the cyclic enamide or
the presence of a heteroatom (O or S) in the beta position
significantly decreased the yield of the coupling reaction
(Scheme 2). We speculated that the use of Ag2CO3 in pure
pivalic acid would facilitate the desired C–H functionaliza-
tion. Indeed, as reported in the literature, the preference
for pivalic acid in comparison to acetic acid, which is less
voluminous, is explained by a greater steric encumbrance
as well as a higher basicity of its conjugate base [10].
Finally, these conditions led to the products 3p–r in
moderate to good yields.
Fig. 1. Representative examples of tetrahydroquinoline derivatives.
tetrahydroquinoline derivative systems, which are omni-
present in various alkaloids, pharmaceutical agents or dye
sensitizers (Fig. 1) [8].
In the light of our recent results in this area [7], we
speculated that we could readily obtain polyfunctionalized
tetrahydroquinoline derivatives from conjugated enam-
ides via Diels–Alder cycloadditions (Fig. 2). The latter could
be generated according to a palladium-catalyzed Fiju-
wara–Moritani reaction, starting from non-aromatic
enamides and activated alkenes. While C-2 functionaliza-
tion was recently developed by direct arylation, especially
in the case of acyclic compounds [9], to the best of our
knowledge, the regioselective C-3 functionalization of
non-substituted enamides has not yet been described,
except in our work [7b].
Keeping in mind that molecular diversity is a perpetual
challenge and having synthesized a range of simple
conjugated enamides, we wished to take advantage of
their reactivity towards the Diels–Alder cycloaddition
reaction in order to generate, in a one-step process, a range
a polyfunctionalized quinoline scaffolds. Diene 3c was
Recent advances in this area have shown that an
oxidant (Cu(OAc)2ÁH2O), a co-oxidant (O2) and an acidic
source are required to perform the direct Fijuwara–
Moritani cross-coupling reaction efficiently. Having estab-
lished the optimal conditions [7b], a variety of enamides
and activated alkenes were found to undergo direct
alkenylation in fair to good yields (Scheme 1). A first
series of ester acrylates was investigated, affording the
desired conjugated enamides 3a–c in good yields. These
newly formed enamides were isolated with an absolute
regio- and stereoselectivity control (E-isomer). Polar
functional groups (sulfonyl, aldehyde, ketone, phospho-
nate or amide) are also tolerated, giving scaffolds 3d–i in
moderate to high yields and demonstrating the potential of
this protocol. More remarkably, starting from methyl
metacrylate, the compound 3j was unfortunately obtained
Scheme 1. Direct coupling involving enamides 1 and alkenes 2.
Fig. 2. Retrosynthetic strategy.

360
N. Gigant et al. / C. R. Chimie 16 (2013) 358–362
Scheme 4. Oxidation of product 4a.
were increased. Using MnO2 led to the aromatized product
5 in good yield (Scheme 4). These results again highlight
the potential of this process in combination with further
conventional transformations.
Scheme 2. Direct coupling involving complex enamides 1 and alkenes 2.
2. Conclusion
In summary, we have developed an efficient synthesis
of conjugated enamides via the Fujiwara–Moritani reac-
tion. This simple and efficient approach was performed
under mild conditions, and tolerated a wide range of
enamides as well as activated alkenes. The synthetic utility
of the dienes obtained was demonstrated via the synthesis
of octahydroquinoline scaffolds via Diels–Alder cycloaddi-
tion. One of the latter intermediates was finally oxidized,
giving the corresponding polyfunctionalized tetrahydro-
quinoline derivative. Further applications of this method-
ology for the generation of suitably functionalized key
scaffolds are in progress and the results of these
investigations will be reported in due course.
then submitted to a series of dienophiles (Scheme 3). The
use of either N-methylsuccinimide or succinimide afforded
the two cycloadducts, 4a and 4b, in high yields, giving
access to the corresponding original functionalized octa-
hydroquinoline skeleton. Performing the cycloaddition
reaction in the presence of maleic anhydride was also
efficient, leading to the desired cycloadduct in 77% yield.
Unfortunately, using 1,4-benzoquinone as dienophile was
unreactive in these conditions, only slight traces of the
desired product were isolated, accompanied by degrada-
tion products.
Finally, in order to obtain tetrahydroquinoline deriva-
tives, cycloadduct 4a, chosen as a model, was submitted to
an oxidative step. Unfortunately, a total lack of reactivity
was observed by using DDQ as the oxidant even when the
loading of oxidant, the reaction time or the temperature
3. Experimental
The infrared spectra of compounds were recorded on a
Thermo Scientific Nicolet iS10. 1H-and 13C-NMR spectra
were recorded on
a spectrometer at 250 MHz (
13C,
62.9 MHz) or 400 MHz (13C, 100 MHz). Chemical shifts
are given in parts per million from tetramethylsilane (TMS)
as an internal standard. Coupling constants (J) are reported
in Hertz (Hz). An electronic ion spray methodology was
used to record mass spectra. All the reagents were obtained
from commercial suppliers unless otherwise stated.
3.1. General experimental procedure
3.1.1. Direct coupling
To a solution of enamide (0.22 mmol) in a mixture
of dimethylacetamide/acetic acid (1:1, 0.60 mL) was
added Pd(OAc)2 (10% mol) followed by Cu(OAc)2ÁH2O
(0.22 mmol) and alkene (0.44 mmol). A slow O2 bubbling
was injected into the solution. The mixture was heated to
70 8C until the disappearance of the starting material. The
reaction was then hydrolyzed by the addition of water. The
aqueous layer was extracted with AcOEt and the combined
organic extracts were washed with a saturated aqueous
solution of NaHCO3, with brine, dried over MgSO4, filtered
and concentrated. The products were purified by flash
chromatography with petroleum ether/ethyl acetate to
yield the desired products.
Scheme 3. Diels–Alder cycloaddition reactions.

N. Gigant et al. / C. R. Chimie 16 (2013) 358–362
361
3.1.2. Diels–Alder reaction
133.3, 135.3, 137.6, 139.9, 168.9, 170.1, 170.9; MS (IS) m/z
To a solution of diene (0.13 mmol) in dry toluene (2 mL)
was added dienophile (0.20 mmol). The mixture was
heated under reflux until the disappearance of the starting
material (TLC control). After the evaporation of the solvent,
the products were purified by flash chromatography with
petroleum ether/ethyl acetate to yield the desired pro-
ducts.
514.0 [M+Na]+.
3.2.4. 1-Benzenesulfonyl-8-methyl-7,9-dioxo-2,3,4,7,8,9-
hexahy dro-1H-pyrrolo[3,4-h]quinoline-6-carboxylic acid
benzyl ester (5)
orange solid; m.p. 81 8C; IR (neat, cm(1) 2926, 1711,
1433, 1162; 1H-MR (250 MHz, CDCl3)
d 1.66 (m, 1H), 1.87
(m, 1H), 2.38 (m, 1H), 2.63 (m, 1H), 3.19 (s, 3H), 3.47 (m,
1H), 3.76 (m, 1H), 5.44 (s, 2H), 7.35–.64 (m, 9H), 7.88 (m,
3.1.3. Oxidation step
2H); 13C-MR (62.5 MHz, CDCl3)
d 21.6, 24.5, 26.6, 45.4,
To
a
solution of octahydroquinoline derivative
68.4, 126.7, 128.6, 128.8, 128.8, 129.0, 129.2, 129.5, 129.8,
133.6, 133.7, 135.3, 135.6, 138.5, 141.5, 165.5, 165.6,
166.0; MS (IS) m/z 491.0 [M+H]+.
(0.07 mmol) in dry CHCl3 (2 mL) was added MnO2
(1.42 mmol). The mixture was heated under reflux until
the disappearance of the starting material (TLC control).
After cooling and filtration on Celite, the solvent was
evaporated. The product was purified by flash chromatog-
raphy with petroleum ether/ethyl acetate to yield the
desired compound.
Acknowledgments
`
´
The MESR (Ministere de l’Enseignement superieur et de
la Recherche) is gratefully acknowledged for the doctoral
followsip to N.G., and the Region Centre and the University
of Orleans for the doctoral followsip to R.R.-R.
3.2. Spectral data of new and representative compounds
3.2.1. 1-Benzenesulfonyl-8-methyl-7,9-dioxo-
´
2,3,4,6,6a,7,8,9,9a, 9b-decahydro-1H-pyrrolo[3,4-
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